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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
considered to have no influence on the outcome
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
yes
Remarks:
considered to have no influence on the outcome
Qualifier:
according to guideline
Guideline:
other: EPA 798.6050 and EPA 798.6400
Deviations:
yes
Remarks:
considered to have no influence on the outcome
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,10-bis(2,2,6,6-tetramethyl-1-piperidinyloxy)-1,10-dioxodecane
EC Number:
417-440-8
EC Name:
1,10-bis(2,2,6,6-tetramethyl-1-piperidinyloxy)-1,10-dioxodecane
Cas Number:
2516-92-9
Molecular formula:
C28 H50 N2 O6
IUPAC Name:
bis(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) decanedioate
Test material form:
solid

Test animals

Species:
rat
Strain:
other: Tif: RAIf (SPF), hybrids of RII/1 x RII/2 (Sprague-Dawley derived)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
Animal Production
CIBA-GEIGY Limited
4332 Stein / Switzerland
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: approx. 5 weeks at delivery
- Weight at study initiation:
145.0-205.5 g in males
122.8-166.5 g in females
- Fasting period before study:
- Housing:
The study was carried out under specified pathogen free (SPF) standard laboratory conditions. The animals were housed in groups of 5 in macrolon cages type 4 with wire mesh tops and standardized granulated soft wood bedding (Societe Parisienne des Sciures Pantin).
- Diet (e.g. ad libitum):
Pelleted, certified standard diet (Nafag No. 8900 FOR GLP) was provided ad libitum (except as noted under Laboratory Investigations). All batches of diet were assayed for composition and contaminant levels by the manufacturer. Analytical results are available at the animal supply office (CIBA-GEIGY Limited, Pharmaceuticals Division).
- Water (e.g. ad libitum):
Tap water was given ad libitum. The drinking water quality fulfilled the critical parameters in the specifications of the "Schweizerisehes Lebensmittelbuch" (Ed. 1972). The results of the routine chemical examination of water at source (Grundwasserfassung Stein) as conducted periodically by the water a u t h o r i t y (Baudepartement des Kantons Aargau, Abteilung Gewaesserschutz) are available to CIBA-GEIGY Limited, as well as the results of inhouse chemical analysis by the analytical laboratories of the Pharmaceuticals Division, CIBA-GEIGY Limited.
- Acclimation period:
An acclimatization period of 10 days was allowed between delivery and start of the treatment. Immediately after delivery, the animals were distributed into groups. In order to set up a fully randomized experiment, they were assigned to these groups by means of computer-generated random numbers. Furthermore, they were weighed during t h i s period.
From the same batch of animals a small number was retained for possible replacement during the acclimatization period. These animals were subjected to identical conditions during this period, and those not used were removed at the start of the experiment.

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2 °C
- Humidity (%): 55 +- 10%
- Air changes (per hr): 16-20 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/day

IN-LIFE DATES: From: January 19, 1995 To: February 28, 1995

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The test article was administered orally by gavage (rubber catheter).
Vehicle:
other: As a standard procedure, distilled water containing 0.5% carboxymethylcellulose and 0.1% Tween 80 was used as a vehicle.
Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Suspensions of the test article in the selected vehicle at the appropriate concentrations were freshly prepared every day immediately prior to the dosing of the animals and administered within about 1 hour.

- VEHICLE
- Justification for use and choice of vehicle (if other than water): standard procedure
- Amount of vehicle (if gavage): 10 ml
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the beginning of the study, suspensions containing the test article at concentrations of 0, 1, 10 and 100 mg/ml vrere analyzed for determination of content, homogeneity and stability.

Control analyses of the test article concentration in the vehicle were carried out at all dose levels on samples collected once per experimental week. The samples were collected on completion of dosing, immediately deep-frozen and sent to the analytical laboratories of Analytical Developtvent AD, CIBA-GEIGY Limited, 4002 Basle / Switzerland. Samples of suspensions containing the test article were analyzed at study days 3, 10, 17 and 24, respectively.

Analytical method: KBB-348/1 (via LC)
Duration of treatment / exposure:
28 days
Frequency of treatment:
1 dose per day, 7 times per week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
TKA 40075 was administered to 5 rats of either sex at dose levels of 10, 100 and 1000 mg/kg body weight.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Dose levels were fixed based on the results of the following previously conducted studies:
Laboratory Study Number 9006-92 Stillmeadow, Inc., Sugar Land, Texas 77478 (USA) Acute oral toxicity study in rats:
LD50 in rats of both sexes: greater than 5050 mg/kg body vreight
and
Test no. 934035: 14-days range finding study in r a t s (gavage) Short/Long-term Toxicology, CIBA-GEIGY Limite, Stein


The treatment was performed on a main group (experimental group I) and a recovery group (experimental group II) of animals for evaluation of toxicity, including laboratory investigations and histopathology. Except for day 1 and week 8 (recovery) examinations, FOB testing was additionally performed with animals of experimental group II .
The same treatment was performed as well on a main group (experimental group III) and a recovery group (experimental group IV) of animals for FOB testing and neuropathology. The surviving animals of experimental group I and III were sacrificed at the end of the treatment period and the surviving animals of experimental group II and IV were sacrificed at the end of the recovery period.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
All animals were checked daily for general appearance, behavior and signs of toxicity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Full assessment of clinical signs was performed once per week and included observation of undisturbed animals in the homecage, close examination during handling and, in cases of abnormal findings, observation in a standard arena. Observations included, but were not limited to, signs of general appearance, alertness when undisturbed, reactivity to handling, autonomic signs, postural and gait abnormalities, and abnormal behavior.

BODY WEIGHT: Yes
- Time schedule for examinations:
The weight of all animals was recorded individually at weekly (midweek) weighing sessions. The first weights were recorded during the acclimatization period. Daily body weights for accurate dosing were measured but not recorded.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not relevant (oral gavage)
The food consumption was recorded weekly (cagewise) and was calculated for periods of one week. The calculation vas based on the weight of the offered diet at the beginning of a weighing period and its difference to the re-weighed amount after several days.
The individual food consumption values were calculated from the food consumption per cage and the number of animals present.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No /

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
Laboratory investigations (hematology, blood chemistry) were carried out on all surviving animals of each dose group of Experimental groups I and II at the end of the treatment period, and additionally at the end of the recovery period on animals of each dose group of Experimental group II kept for reversibility evaluation.
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Not specified
- How many animals: all surviving animals
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
Laboratory investigations (hematology, blood chemistry) were carried out on all surviving animals of each dose group of Experimental groups I and II at the end of the treatment period, and additionally at the end of the recovery period on animals of each dose group of Experimental group II kept for reversibility evaluation.
- Animals fasted: Not specified
- How many animals: all surviving animals
- Parameters checked in table 2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
1, 6, and 24 hour after the first administration of TKA 40075 and at the end of weeks 1, 2 and 4 and at the end of week 8 for recovery animals)
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 3)

HISTOPATHOLOGY: Yes (see table 4)
Statistics:
For each time point and parameter an univariate statistical analysis was performed. Nonparametric methods were applied, to allow for non normal as well as normal data distribution.
Each treated group was compared to the control group either by Lepage's or by Wilcoxon's two-sample test and tested for increasing or decreasing trends from control up to the respective dose group by Jonckheere's test for ordered alternatives. The Lepage test is a combination of Wilcoxon and Ansari-Bradley statistics, i.e. a combined test for location and dispersion. The Lepage test has a good power against the more general alternative that the distributions differ not only in location but also in dispersion. The Jonckheere test is sensitive to monotone dose-related effects.

Statistical significance does not necessarily imply biological relevance. Hence, the responsible scientist may not comment on statistically significant values lying within the physiological range and on the other hand may comment on values, which differ substantially from the expected normal values although this difference was not statistically significant.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related clinical signs were observed during the study, except for piloerection, cyanosis, dyspnea and respiratory sounds recorded for one moribund female of group 3 (200 mg/kg) which had to be sacrificed on study day 2. However, as these signs were observed only in one single female of the intermediate dose group, no toxicological relevance was attributed to them.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No treatment-related death occurred during the study.
One female of group 3 (no. 138, 200 mg/kg) had to be sacrificed in moribund condition at day 2. The isolated and very early onset of the moribund condition of this animal is considered to be unrelated to treatment.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The body weight development of treated male and female groups was not influenced by treatment.
In absence of a dose dependency, minimally increased mean body weights recorded for male groups 2 and 3 (50 and 200 mg/kg) and female group 3 (200 mg/kg) are considered to be of no toxicological relevance but to reflect normal biological variability of this parameter.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no relevant differences in mean food consumption between treated groups and controls.
No experimental relevance was attributed to the minimally increased diet intake noted for female group 3 (200 mg/kg), particularly as there was no dose-relationship.
Food efficiency:
no effects observed
Description (incidence and severity):
Mean food consumption ratios of treated groups were comparable to those of the control groups.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In male animals of group 4 (1000 mg/kg) erythrocyte count, hemoglobin concentration and hematocrit were slightly lower at treatment end. The changes were fully reversible after the recovery period.
All other minor differences between control and treated groups attaining a level of statistical significance are considered to reflect the physiological variation of the parameters, and were therefore considered not treatment-related.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The following minor and reversible alterations of blood chemistry parameters were observed in animals of group 4 (1000 mg/kg) at treatment end:
Plasma albumin and total protein levels were minimally decreased in males, plasma potassiiom and calcium concentrations were slightly increased in females.
Lower activities of alanine aminotransferase as recorded for male animals of group 4 at treatment end are without toxicological relevance.

All other minor differences between control and treated groups attaining a level of statistical significance represent the physiological variation of the parameters, and were therefore considered not treatment-related.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Observations and functional tests conducted on 10 animals of each sex and group at 1, 6, and 24 hour after the first administration of TKA 40075 did not show any indication of a potential acute neurotoxicity. Observations and functional t e s t s conducted on 15 animals of each sex and group at the end of weeks 1, 2 and 4, and on 5 animals of each sex and group at the end of week 8 (recovery animals), respectively, provided no evidence for a potential neurotoxicity after repeated administration (delayed effects).

In males only, repeated measures ANOVA on data from day 1 (acute effects) indicated a significant contrast of group 4 vs 1 on hindlimb grip strength. MULTTEST procedures indicated that this effect was due to a slight decrease at 1 hour after administration. Since this effect was observed in males only, was transient, and was not accompanied by a concomitant increase in landing foot splay, it was considered as incidental rather than a compound-related adverse effect.

Statistical evaluation of data of week 1 through 4 (delayed effects) using repeated measures ANOVA indicated effects in males only. A significant TIME*GROUP interaction was obtained for body temperature (significant contrast of group 3 vs 1), while landing foot splay just failed to reach the level of significance. MULTTEST procedures indicated that the effect on temperature was due to higher pretest values in group 3 and was thus not considered to be relevant. The effect on landing foot splay was traced back to a slight increase in group 4 values at week 1. Since this effect was no longer seen at later time points and not accompanied by decreased grip strength values, it was not considered to be of toxicological relevance.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):

At the end of the treatment period, organ weight analysis revealed the following reversible differences to the controls:
slightly increased absolute and relative kidney weights in male group 4 (1000 mg/kg) achieving levels of statistical significance;
minimally, although statistically significantly increased liver to body weight ratio for males of group 4 (1000 mg/kg);
significantly decreased absolute and relative liver weights of females treated at 1000 mg/kg.

As values recorded were within the range of historical controls, no toxicological relevance was attributed to the significantly increased mean kidney weight of male group 3 (200 mg/kg) nor to the significantly decreased relative kidney weights of female groups 2 and 4 (50 and 1000 mg/kg), respectively.
Equally, the increased adrenal weights and/or ratios recorded for males of groups 3 and 4 (200 and 1000 mg/kg), as well as the statistically decreased liver to body weight ratio of female group 3 (200 mg/kg) are within the normal weight range and therefore considered unrelated to treatment.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
One out of five male rats of group 4 (1000 mg/kg) presented with one small testis and in 1/5 males of group 3 (200 mg/kg), the testes were reported to be bilaterally small at the end of treatment (experimental group I). Microscopically, these findings corresponded with a tubular atrophy of the testes, which was not considered treatment-related.
The few macroscopically observed changes in the recovery groups (experimental group II) were similar to those occurring spontaneously in our colony of rats. According to the study protocol, these macroscopical changes were not examined histopathological ly, and, therefore, no microscopical
correlations were made.
Neuropathological findings:
no effects observed
Description (incidence and severity):
Macroscopical examination did not reveal any treatment-related changes of tissues sampled for neuropathological examination.
Microscopical examination of the eyes, optic nerves, and multiple areas of the central and peripheral nervous system of the male and female animals of control and high-dose groups did not reveal any treatment-related neuropathic changes. All microscopical slides presented normally distributed and well preserved nerve cells and nerve fibers as well as the glia cells and other supporting tissues.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The epithelium of renal tubules in the kidneys revealed a minimal hyaline change in 1/5 males of group 4 (1000 mg/kg) and a moderate hyaline change in two males of this group. This finding was, therefore, present in group 4 males in a minimally increased incidence and severity when compared to controls. This change consisted of eosinophilic droplets within the cytoplasm of proximal convoluted tubules as the result of an accumulation of alpha-2-microglobulin which is synthesized and secreted by the liver. This protein is normally present as eosinophilic granules within phagolysosomes in renal tiibules of sexually mature male rats. One proposed mechanism of accumulation suggests the test article or a metabolite to bind with the protein or to alter the structure so that the tubular cell lysosomal erazymes cannot degrade the protein complex.
The microscopical findings observed in female rat no. 138 of group 3 (200 mg/kg), which had to be sacrificed in moribund condition on study day 2, included a moderate cytoplasmic vacuolization of centrilobular liver hepatocytes with secondary hepatocellular single cell necrosis. These liver lesions were regarded to be of degenerative origin, probably consequent to circulatory disturbances. Since these changes were present in only one female and such lesions sporadically and spontaneously occur in our colony of rats, no toxicological relevance was attributed to them.

After the recovery period, the finding of hyaline change in renal tubular epithelium was present in an incidence and severity being within the range seen in controls and other dose groups. Therefore, this finding was considered to be fully reversible within 4 weeks of recovery.
Additionally, a variety of other changes was found in this study. They commonly occur in our colony of rats, and, neither their incidences nor their distribution and morphologic appearance gave any indication of a treatment-related associa- tion.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
food efficiency
gross pathology
haematology
histopathology: neoplastic
histopathology: non-neoplastic
mortality
neuropathology
organ weights and organ / body weight ratios
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
histopathology: non-neoplastic
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

Under the conditions of this test, treatment with TKA 40075 resulted in minimal or slight reversible changes to the kidney and liver at the high dose level (1000 mg/kg) as evidenced by changes in organ weights, alterations in blood chemistry parameters and histopathological findings in the kidney. Additionally, slightly decreased values for some red blood cell parameters were noted for males of group 4 (1000 mg/kg).

Neurotoxicological examinations (FOB testing and neuropathology) revealed no neurotoxic effects of the test article.

Considering the minimal and slight extent of effects observed as well as their complete reversibility, no toxicological importance is attributed to these findings. Therefore, for both sexes a dose level of 1000 mg/kg body weight per day is regarded to represent the "no observable adverse effect level" (NOAEL) for TKA 40075 when administered by daily oral gavage for 28 days.

Based on the above results, the "no observable effect level" (NOEL) is defined as 200 mg/kg body weight per day for animals of both sexes.

Applicant's summary and conclusion

Conclusions:
Considering the minimal and slight extent of effects observed as well as their complete reversibility, no toxicological importance is attributed to these findings. Therefore, for both sexes a dose level of 1000 mg/kg body weight per day is regarded to represent the "no observable adverse effect level" (NOAEL) for TKA 40075 when administered by daily oral gavage for 28 days (OECD 407).
Based on the above results, the "no observable effect level" (NOEL) is defined as 200 mg/kg body weight per day for animals of both sexes.
Executive summary:

The test article TKA 40075 was administered by gavage for 4 weeks at daily doses of 0, 50, 200 and 1000 mg/kg body weight to a total of 160 albino r a t s . In each dose group, 10 animals per sex (5 animals each of experimental groups I and III, respectively) were sacrificed at the end of the treatment period. Additionally, 10 animals per sex and group (5 animals each of experimental groups II and IV, respectively) were kept for a 4-week recovery period before sacrifice.

Evaluation of general toxicology including laboratory investigations and histopathology was performed with animals of experimental groups I and I I . Additionally, functional observational battery (FOB) testing was conducted with animals of experimental group II at pre- test, week 1, 2 and 4, respectively. Neurotoxicological examinations including FOB testing and neuropathology were conducted with animals of experimental groups III and IV.

Administered quantities of the test article suspension were adjusted daily to individual body weight.

The results of this study are summarized as follows:

In-life observations

No clinical signs of toxicological relevance were observed during the study.

Functional observational battery

Observations and functional tests conducted on 10 animals of each sex and group at 1, 6, and 24 hours after the first administration of TKA 40075 did not show any indication of a potential acute neurotoxicity. Observations and functional tests conducted on 15 animals of each sex and group at the end of weeks 1, 2 and 4, and on 5 animals of each sex and group at the end of week 8 (recovery animals) , respectively, provided no evidence for a potential neuro-toxicity after repeated administration (delayed effects).

Mortality

No treatment-related death occurred during the study.

Body weight

The body weight development of treated male and female groups was not influenced by treatment.

Food consumption

There were no relevant differences in mean food consiimption between treated groups and controls.

Food consumption ratios

Mean food consumption ratios of treated groups were comparable to those of the control groups.

Hematology

At treatment end, the following fully reversible changes were recorded for males of group 4 (1000 mg/kg): slightly decreased values for erythrocyte count, hemoglobin concentration and hematocrit.

Blood chemistry

The following minor and reversible alterations of blood chemistry parameters were observed in animals of group 4 (1000 mg/kg) at treatment end: minimally decreased plasma albumin and total protein levels in males, and slightly increased potassium and calcium concentrations in females, respectively.

Organ weights

At treatment end, the following reversible changes were found in animals treated at 1000 mg/kg: slightly increased absolute and relative kidney weights in males, minimally increased relative liver weight in males, and significantly decreased absolute and relative liver weights in females, respectively.

Pathology

The macroscopical examination revealed no treatment-related changes. At microscopical examination, a hyaline change of renal tubular epithelium was present in male rats of group 4 in a minimally increased incidence and severity. This increase was reversible within 4 weeks of recovery.

Neuropathology

Microscopical examination of the eyes, optic nerves, and multiple areas of the central and peripheral nervous system of the male and female animals of control and high-dose groups did not reveal any treatment-related neuropathic changes.

Conclusion

Under the conditions of this test, treatment with TKA 40075 resulted in minimal or slight reversible changes to the kidney and liver at the high dose level (1000 mg/kg) as evidenced by changes in organ weights, alterations in blood chemistry parameters and histopathological findings in the kidney. Additionally, slightly decreased values for some red blood cell parameters were noted for males of group 4 (1000 mg/kg).

Neurotoxicological examinations (FOB testing and neuropathology) revealed no neurotoxic effects of the test article.

Considering the minimal and slight extent of effects observed as well as their complete reversibility, no toxicological importance is attributed to these findings. Therefore, for both sexes a dose level of 1000 mg/kg body weight per day is regarded to represent the "no observable adverse effect level" (NOAEL) for TKA 40075 when administered by daily oral gavage for 28 days.

Based on the above results, the "no observable effect level" (NOEL) is defined as 200 mg/kg body weight per day for animals of both sexes.